The main objectives of this research proposal are to determine the sequence of morphological and biochemical alterations during cellular injury following myocardial ischemia or anoxia, to define criteria of irreversible injury and to prevent these changes by drug interventions. The intracellular ionic redistribution has a major impact on the cell necrosis as is supported by our studies on calcium paradox. The main effect of Ca ions deprivation is the cell separation and tearing of the gap junctions which lead the way to Ca ions influx upon reperfusion with Ca ions. The latter phenomenon appeared to be crucial to pathogenesis of permanent cell injury in Ca ions paradox and myocardial ischemia and reflow. The route of excessive Ca ions accumulation was prevented by a Ca ions channel blocker, diltiazem, through preservation of cell junctions and gap junctions. Therefore, we will investigate the effects of this drug on dog or pig hearts. We plan to quantitate the degree of damage with transmission electron microscopy, ionic redistribution with x-ray microanalysis technique and, finally, effects of therapeutic interventions alleviating the effects of Ca ions overload, energy exhaustion and electrolyte imbalance.